The present invention relates to the method of use of styrene derivatives to treat inflammation, immunological diseases, or diabetes.
The present invention is based on the crucial role played by signaling pathways in affecting the function of cytokines. Cytokines are molecules secreted by immune cells and are important in mediating immune responses. Cytokines effect their functions at the site of secretion or at distant sites. Cytokines initiate their responses by binding to their respective receptors. This receptor-ligand interaction induces a signal and leads to the transcription of new genes that change the functional capacity of the target cell. Thus the effect of cytokines may result in the secretion of other cytokines, altered cellular function, cell division or differentiation. In most immune cells (T, B and macrophages) cytokine receptors themselves act as protein tyrosine kinases that are phosphorylated upon ligation of the receptor or are closely linked to phosphotyrosine kinases (PTK""s).
Inhibitors of PTK function are known, such as querestin, the first one which was isolated. Querestin was found to inhibit not only PTK""s but other enzymes such as cAMP dependent kinase, protein kinase C (PKC) and ATP requiring enzymes. Other naturally occurring compounds such as erbastatin, herbamycin and levandestin affect predominantly the function of PTK""s and have been termed tyrphostins. Most tyrphostins are 100-1000 fold more potent in inhibiting PTK""s than PKA, PKC or other calcium dependent kinases. So far the role of tyrphostins has focused on their potential application in neoplastic diseases. A recent therapeutic test of tyrphostins has been in the treatment of acute lymphoblastic leukemia, in which a known JAK2 kinase inhibitor was shown to inhibit the proliferation of leukemic cells without affecting mitogen-induced T cell proliferation.
The present invention is directed to treatment of immunological diseases or inflammation. The principal elements of the immune system are macrophages or antigen-presenting cells, T cells and B cells. The role of other immune cells such as NK cells, basophils, mast cells and dendritic cells are known, but their role in primary immunologic disorders is uncertain. Macrophages are important mediators of both inflammation and providing the necessary xe2x80x9chelpxe2x80x9d for T cell stimulation and proliferation. Most importantly macrophages make IL 1, IL 12 and TNFxcex1 all of which are potent pro-inflammatory molecules and also provide help for T cells. In addition, activation of macrophages results in the induction of enzymes, such as cyclooxygenase II (COX II), nitric oxide (NO) and other free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFNxcex3). It is believed that PTK""s and other undefined cellular kinases are involved in the activation process.
Macrophages take up and break down antigens into small fragments. These fragments then associated with the major histocompatibility complex II (MHC II). This complex of antigen fragments and MHC II is recognized by the T cell receptor. In association with appropriate co-stimulatory signals this receptor-ligand interaction leads to the activation and proliferation of T cells. Depending on the route of administration of antigen, their dose and the conditions under which macrophages are activated, the immune response can result in either B cell help and antibody production or on the development of cell mediated response. Since macrophages are sentinel to the development of an immune response, agents that modify their function specifically their cytokine secretion profile are likely to determine the direction and potency of the immune response.
This invention is directed to a method of treating immunological diseases, inflammation, or Type I and Type II diabetes with compounds of formula I shown below. The compounds inhibit the secretion of pro-inflammatory cytokines and thus prevent the development or inhibit established inflammatory responses. 
wherein A and C are independently H, alkyl of 1-6 carbon atoms, hydroxy, or alkoxy of 1-6 carbon atoms;
B is hydroxy, alkoxy of 1-6 carbon atoms, xe2x80x94CO2Z, O(CH2)mCO2Z, xe2x80x94SO3Z, xe2x80x94OPO3Z2; and
Y is cyano, 
or
xe2x80x94C(NR1 R2)xe2x95x90C(CN)2;
wherein Xxe2x95x90O or S, and R1 and R2 are independently
H, benzyl, xe2x80x94CH(CH3)C6H6,
xe2x80x94(CH2)n C6H6, phenyl; xe2x80x94CO2R;
n=2-4; R is lower alkyl of 1-6 carbon atoms;
m=1-4 and
Z is H, a cation or lower alkyl of 1-6 carbon atoms.